Drug design and discovery最新文献

The herpesvirus maturational proteinase, called assemblin, is essential for the production of infectious virus and represents a new molecular target for the development of antivirals. A brief summary of the synthesis, structure, and function of this fascinating enzyme is presented here.

The relationship between the chemical structure and the HIV-1 RT inhibitory activity has been studied for a series of quinoline derivatives. Two methods were used: a standard QSAR analysis, by combining the methods of Hansch and Free-Wilson, and an analysis using quantum chemistry indices as descriptor parameters, by the semiempirical method AM1. The equations obtained lead to the proposal that the activity of the compounds increases, mainly, with the presence of electron-withdrawing substituents in position 6 of the quinoline ring that cause a decrease in the energy from the molecular orbital LUMO. In turn, this fact leads to the proposal that the most important interaction of these compounds with the HIV-1 RT is a charge transfer type interaction, with the quinoline aromatic ring acting as acceptor.

A series of thienocycloheptapyridazines (3aa-dd), structurally related to Minaprine, was synthesized and compounds tested for their affinity towards muscarinic receptors. All of them showed Ki values in the micromolar range towards both the antagonist 3H-QNB and the agonist 3H-OXO-M, thus indicating that they act as antagonists at the muscarinic receptors. Moreover a theoretical study was performed on their interaction behaviour with a three dimensional (3-D) model of the human m1 muscarinic receptor.

The synthesis and preliminary evaluation of new quinoline and quinoxaline derivatives (obtained by applying the original Reissert method, conveniently modified) as HIV-1 Reverse Transcriptase (RT) inhibitors are presented in this paper; likewise, the first structure-activity relationships are also proposed. Propyl 2-cyano-1(2H)-quinolin-carboxylate 2e, isopropyl 2-cyano-1 (2H)-quinolincarboxylate 2f, butyl 2-cyano-1 (2H)-quinolincarboxylate 2g and isobutyl 2-cyano-1 (2H)-quinolincarboxylate 2h have been selected as lead compounds. These compounds are active against the HIV-1 RT mutant type P236L (2f, IC50 = 1.2 microM) and present activity as anti-infective agents in HLT41acZ-1IIIB cells, showing no cytotoxicity at the active concentrations.

The synthesis and preliminary evaluation of new benzo[f]quinoline and pyridine derivatives, obtained by application of the Reissert method and its modifications, as HIV-1 RT inhibitors and anti-infectives are presented. The most active products against HIV-1 RT wild type are the ethyl 2-cyano-1,2-dihydrobenzo[f]quinoline-1-carboxylate 2b, propyl 2-cyano-1,2-dihydrobenzo[f]quinoline-1-carboxylate 2c, and 2-cyano-1-(2'-furoyl)-1,2-dihydrobenzo[f]quinoline 2n, which maintain their activity against the mutant type P236L, resulting inactive against the Y181C type. Using the data previously obtained by our research team for analogous series derived from quinoline as reference, the compounds which have now been obtained present an increase in the cytotoxic character attributable to the introduction of a benzene ring fused with the quinoline base nucleus, as well as a decrease of the activity as HIV-1 RT inhibitors when the quinoline benzenic ring is eliminated.

A GnRH-neutralising vaccine, with potential applications in the treatment of human sex hormone-dependent disorders, was developed by conjugating GnRH-glycys to tetanus toxoid. An evaluation of adjuvant, dose and carrier pre-sensitisation was made. Male rats immunised with the conjugate, adsorbed onto alum, showed higher anti-GnRH antibody levels and suppressed testosterone concentrations, compared with animals immunised without adjuvant. Conjugate administration in a four injection regime proved to be the most effective in disrupting fertility, as assessed by the degree of lowered testosterone levels and gonadal atrophy. Pre-sensitisation with tetanus toxoid had an initial marked effect on immunisation, observed following 2 drug doses; the pre-sensitised animals showed a lower antibody response to the conjugate than did the non-primed animals. However, as the number of drug doses increased to 4, there was no significant difference between the primed and non-primed animals.

Three-dimensional molecular models of the human melanocortin receptor (hMC1R) have been developed based upon the electron cryo-microscopic structure of bacteriorhodopsin and the electron density footprint of bovine rhodopsin. alpha-Melanocyte-stimulating hormone, Ac-Ser-Tyr-Ser-Met4-Glu-His-Phe7-Arg-Trp-Gly-Lys-Pro-Val-NH2 (alpha-MSH, alpha-melanotropin), and the superpotent, prolonged acting agonists, Ac-Ser-Tyr-Ser-Nle4-Glu-His-DPhe7-Arg-Trp-Gly-Lys-Pro-Val-NH2 (NDP-MSH) and Ac-Nle4-c[Asp5-His6-DPhe7-Arg8-Trp9-Lys10]-NH2 (MTII), have been modeled into the proposed binding sites with specific ligand-receptor interactions identified. The melanotropin sidechain pharmacophores, DPhe7 and Trp9, are proposed to interact with a hydrophobic network of receptor aromatic residues in transmembrane regions 4, 5, 6, and 7. In addition, a hydrophilic network involving the ligand Arg8 and polar receptor residues located in transmembrane regions 2 and 3 were identified. Biological studies on alpha-MSH, NDP-MSH, MTII, and related peptides have been correlated with the proposed hMC1R model in terms of agonism, affinity, and prolongation. Finally, limited MC1R mutagenesis studies comparing alpha-MSH and NDP-MSH are interpreted within the context of the proposed hMC1R models.

Although many physicochemical properties of chemically diverse nonnucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) differ, there is a common three-dimensional feature. This shape is a rigid butterfly-like configuration which fits well into a sizable internal cavity of the allosteric area of the enzyme. The number of amino acids of the allosteric receptor sites that contribute to NNRTIs binding correlates with the degree of the butterfly-like shape. It seems that molecular rigidity of the butterfly-like shape, the drug affinity and the probability of resistance development are closely related.

A large, highly hydrophilic and constrained omega-loop was dissected from the allosteric area of HIV-1 reverse transcriptase (segment Tyr181 to Tyr188). The loop contains two amino acids (Asp185, Asp186) of the catalytic aspartyl triad (Asp110, Asp185, Asp186) and two amino acids (Tyr181, Tyr188) of the nonnucleoside RT inhibitor (NNRTI) binding sites. Hydrogen-bonding forces between the two folded peptide chains play the greatest role in holding the two chains together and in specifying the folding patterns. The treatment of solvents as dielectric continuums surrounding the AMBER force field model has shown changes in conformation but these changes were not dramatically because the omega-loop shape was completely maintained.

Using the molecular "cloud" of the HIV-1 reverse transcriptase (RT) as starting point, the peptide backbone of the polymerase subunit was visualized by molecular modelling. Then, the two subregions 98-106 and 179-190 of the allosteric area were "isolated". From the latter subregion, the Tyr181 to Tyr188 segment containing two amino acids (Asp185, Asp186) of the catalytic aspartyl triad and two amino acids (Tyr181, Tyr188) of the nonnucleoside RT inhibitor (NNRTI) binding sites, was excised. It was shown that the segment has a omega-like loop configuration which is highly hydrophilic. The two phenolic side chains of Tyr181 and Tyr188 represent the lipophilic "horizontal axes" of the omega-loop shape. The relative rigidity of the omega-loop is mainly based on a hydrogen bond between the peptide CO of Tyr181 and the peptide NH of Tyr188. Solvation in water increases the number of intramolecular hydrogen bonds. Therefore, desolvation is one of the conditions of binding with NNRTIs. Site-directed mutagenesis affects the hydrophilicity of the omega-loop while steric features are less influenced.